Histone deacetylase compositions and uses thereof

Abstract

The present invention is based, at least in part, on the discovery that fragments of the histone deacetylase 4 (HDAC4) gene lacking the enzymatic domain promoted rod survival when electroporated into the retinas of a relevant mouse model of retinitis pigmentosa. Specifically, it has been discovered that only a small portion of the N-terminus of HDAC4 promotes survival of rod cells in rd1 mice. Accordingly, the present invention provides histone deacetylase 4 compositions and methods of use thereof for inhibiting neuronal cell death, e.g., retinal cell death.

1 . A pharmaceutical composition suitable for intraocular administration, comprising
 (a) an isolated HDAC4 nucleic acid molecule comprising nucleotides 793-1416 of SEQ ID NO:1, nucleotides 793-1170 of SEQ ID NO:1, nucleotides 793-1146 of SEQ ID NO:1, or nucleotides 978-1257 of SEQ ID NO:1;   (b) an isolated HDAC4 nucleic acid molecule encoding a peptide comprising amino acid residues 1-208 of SEQ ID NO:2, amino acid residues 1-126 of SEQ ID NO:2, amino acid residues 1-118 of SEQ ID NO:2, or amino acid residues 62-155 of SEQ ID NO:2; or   (c) an isolated HDAC4 peptide comprising amino acid residues 1-208 of SEQ ID NO:2, amino acid residues 1-126 of SEQ ID NO:2, amino acid residues 1-118 of SEQ ID NO:2, or amino acid residues 62-155 of SEQ ID NO:2.   
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . A composition comprising a viral vector comprising a retinal cell-type specific promoter operably linked to
 (a) an HDAC4 nucleic acid molecule comprising nucleotides 793-1416 of SEQ ID NO:1, nucleotides 793-1170 of SEQ ID NO:1, nucleotides 793-1146 of SEQ ID NO:1, or nucleotides 978-1257 of SEQ ID NO:1; or   (b) a nucleic acid molecule encoding an HDAC4 peptide comprising amino acid residues 1-208 of SEQ ID NO:2, amino acid residues 1-126 of SEQ ID NO:2, amino acid residues 1-118 of SEQ ID NO:2, or amino acid residues 62-155 of SEQ ID NO:2.   
     
     
         5 . (canceled) 
     
     
         6 . The composition of  claim 4 , wherein the retinal cell-type specific promoter is a rod-specific promoter, a cone-specific promoter, or a rod- and cone-specific promoter. 
     
     
         7 .- 9 . (canceled) 
     
     
         10 . A method of inhibiting neuronal cell death, comprising contacting said cell with
 (a) an isolated HDAC4 nucleic acid molecule comprising nucleotides 793-1416 of SEQ ID NO:1, nucleotides 793-1170 of SEQ ID NO:1, nucleotides 793-1146 of SEQ ID NO:1, or nucleotides 978-1257 of SEQ ID NO:1;   (b) an isolated nucleic acid molecule encoding an HDAC4 peptide comprising amino acid residues 1-208 of SEQ ID NO:2, amino acid residues 1-126 of SEQ ID NO:2, amino acid residues 1-118 of SEQ ID NO:2, or amino acid residues 62-155 of SEQ ID NO:2; or   (c) an isolated HDAC4 peptide comprising amino acid residues 1-208 of SEQ ID NO:2□ amino acid residues 1-126 of SEQ ID NO:2, amino acid residues 1-118 of SEQ ID NO:2, or amino acid residues 62-155 of SEQ ID NO:2, thereby inhibiting death of the neuronal cell.   
     
     
         11 . A method for treating or preventing a neurodegenerative disorder in a subject comprising administering to said subject
 (a) an isolated HDAC4 nucleic acid molecule comprising nucleotides 793-1416 of SEQ ID NO:1, nucleotides 793-1170 of SEQ ID NO:1, nucleotides 793-1146 of SEQ ID NO:1, or nucleotides 978-1257 of SEQ ID NO:1;   (b) an isolated nucleic acid molecule encoding an HDAC4 peptide comprising amino acid residues 1-208 of SEQ ID NO:2, amino acid residues 1-126 of SEQ ID NO:2, amino acid residues 1-118 of SEQ ID NO:2, or amino acid residues 62-155 of SEQ ID NO:2; or   (c) an isolated HDAC4 peptide comprising amino acid residues 1-208 of SEQ ID NO:2, amino acid residues 1-126 of SEQ ID NO:2, amino acid residues 1-118 of SEQ ID NO:2, or amino acid residues 62-155 of SEQ ID NO:2, thereby treating or preventing the neurodegenerative disorder in the subject.   
     
     
         12 .- 15 . (canceled) 
     
     
         16 . The method of  claim 10  or  11 , wherein the nucleic acid molecule encodes a peptide localized to the cytoplasm of the neuronal cell or the peptide is localized to the cytoplasm of the neuronal cell. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 10 , wherein the cell is a retinal cell. 
     
     
         20 . The method of  claim 19 , wherein the retinal cell is a bipolar cell, a rod photoreceptor cell and/or a cone photoreceptor cell. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 10 , wherein the neuronal cell death is naturally occurring. 
     
     
         24 . The method of  claim 10 , wherein the neuronal cell death is caused by a neurodegenerative disorder. 
     
     
         25 . The method of  claim 11  or  24 , wherein the neurodegenerative disorder is age-related macular degeneration. 
     
     
         26 . The method of  claim 11  or  24 , wherein the neurodegenerative disorder is retinitis pigmentosa. 
     
     
         27 .- 31 . (canceled) 
     
     
         32 . The method of  claim 10 , wherein the contacting is within the eye of a subject. 
     
     
         33 . The method of  claim 11 , wherein the administration is intraocular administration.